Project Summary/Abstract: Bacterial pneumonia is frequently complicated by lung injury and the acute respiratory distress syndrome (ARDS), which is a major cause of morbidity and mortality in critically ill patients. Platelet deficiency, or thrombocytopenia, is an independent risk factor for increased mortality in patients with ARDS and severe pneumonia but it is not known if this association is causal or indirect. Mouse models of bacterial pneumonia support a causal host-protective role for platelets although the mechanisms are unclear. Platelets, when activated, release numerous factors that may support repair of lung injury and host defense against invading pathogens. Thrombospondin- 1 (TSP-1) is the most abundant platelet granule protein and has been shown to modulate proteolysis, which may be crucial to propagating repair after lung injury. TSP-1 is also a ligand for the scavenger receptor, CD36, which can support the host response to pathogens during acute lung infection. The platelet TSP-1-CD36 pathway has been shown to support thrombus stability but little is known about whether platelet CD36 contributes to host protection during lung injury. The main objective of this proposal is to determine the role of platelet granule factors in repairing lung injury and whether the TSP-1-CD36 platelet pathway is involved in lung injury repair and pathogen defense in the lungs. Using combined pneumonia and platelet transfusion models, two aims will be studied. Aim 1 will determine the contribution of platelet signaling, platelet granule release, and platelet TSP-1 during intrapulmonary infection with Pseudomonas aeruginosa utilizing platelet deficient mice. Aim 2 will determine whether platelet CD36 activation modulates platelet activity in response to pathogen exposure, and supports repair and optimal pathogen control in the lung. By improving understanding of platelet-mediated protective mechanisms during pathogen-triggered lung injury, this project may help to provide rational therapeutic strategies to improve morbidity and mortality of critically ill patients. Furthermore, this project will provide the applicant the opportunity to develop expertise as a physician-scientist in pulmonary host defense. The training plan will promote acquisition of advanced laboratory skills including specialized quantitative imaging of platelet action in response to pathogen exposure. Combined with close mentoring and immersion in the robust research environment of the University of Pittsburgh, this proposal will support the candidate?s development as an independent physician- scientist investigator.